Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo.

Abstract

IntroductionTumors frequently induce the multifunctional cytokine IL-6, which has been linked to several paraneoplastic syndromes, most notably cachexia. IL-6 stimulates osteoclast formation, causes mild hypercalcemia, and is produced by bone cells in vitro upon exposure to systemic hormones. Since IL-6 is produced together with parathyroid hormone-related protein (PTH-rP) in some patients with cancer, we tested the hypothesis that production of IL-6 potentiates the effects of Invest. 1995Invest. . 95:2846Invest. -2852

Parathyroid hormone‐related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia

“…Consistent with this notion, de la Mata et al have demonstrated that IL-6 enhances PTH-rPinduced hypercalcemia in human lung carcinoma. 16 However, regardless of the role IL-6 plays in TIH, the results of the current study suggest that serum IL-6 is an additional indicator for TIH in patients with lung carcinoma.…”

“…These cytokines also are implicated in the pathogenesis of TIH. Furthermore, IL-1␤ 16,17 and IL-6 18 have been shown to enhance PTH-rP-induced bone resorption and hypercalcemia. Of note, these hypercalcemic patients also exhibited higher serum levels of IL-6 compared with nonhypercalcemic patients (35.5 Ϯ 7.2 pg/mL vs. 2.8 Ϯ 0.7 pg/mL [mean Ϯ SE]; P Ͻ 0.001) (Fig.…”

Mechanisms of cancer metastasis to the bone

“…IL-6 is constitutively expressed by renal, bladder, prostate, cervical, glioblastoma and breast carcinoma cells and immunohistochemical studies have demonstrated IL-6 expression in the cytoplasm of colon, prostate and breast carcinoma cells [15,16,17,18]. IL-6 is a potent stimulator of osteoclast formation and can enhance the effects of PTHrP on osteoclasts [19,20]. Breast cancer cells also produce IL-1, TNF and prostaglandins which increase RANKL expression and stimulate osteoclasts [21,22].…”

Medroxyprogesterone acetate inhibits interleukin 6 secretion from KPL-4 human breast cancer cells both in vitro and in vivo: a possible mechanism of the anticachectic effect

“…A number of studies have been conducted to explore the factors responsible for this cachexia, and it has been revealed that elevated blood levels of tumour necrosis factor α (TNF-α), interleukin 1 (II-1), IL-6, IL-11, γ-interferon, leukaemia inhibitory factor or 24 kDa proteoglycan may induce cachexia (Beutler et al, 1986;Moldawer et al, 1988;Metcalf et al, 1990;Matthys et al, 1991;Strassmann et al, 1992a;Ohsumi et al, 1994;Todorov et al, 1996). One of these factors, IL-6, is a pleiotropic cytokine physiologically involved in the differentiation of myeloid and neuronal cells, and pathologically involved in the early host response to infection and injury (Kishimoto, 1989), in the proliferation of myeloma (Kawano et al, 1988), urological cancer cells (Miki et al, 1989;Okamoto et al, 1997a,b) and possibly breast cancer cells (Chiu et al, 1996), and in the development of hypercalcaemia and osteolytic metastases (De La Mata et al, 1995). A series of studies have suggested that IL-6 secreted from tumour cells is one of the cachectic factors in animal models of murine colon cancer or of xenograft tumours in athymic nude mice (Greenberg et al, 1992;Strassmann et al, 1992b;Ohe et al, 1993;Fujimoto-Ouchi et al, 1995;Yasumoto et al, 1995;Billingsley et al, 1996;Kajimura et al, 1996;Mori et al, 1996;Ohira et al, 1996;Tsujinaka et al, 1996).…”